The present invention relates to preparation of 7-amino-3-(2-furanylcarbonylthiomethyl)-3-cephem-4-carboxylic acid of the formula 
Herein further referred to as Furaca, which is a key intermediate useful in the manufacture of ceftiofur, a cephalosporin antibiotic used for treating bovine respiratory disease.
Process or making ceftiofur intermediate by a novel route in high yield and high purity.
U.S. Pat. No. 4,464,367 by Labeeuw teaches a process of preparation of ceftiofur. Ceftiofur was synthesized by condensing activated syn isomer of (2-tritylamino-4-thiazolyl)-2-methoxyimino acetic acid of the formula 
with Furaca in presence of triethylamine to yield tritylceftiofur which on further treatment with aqueous formic acid yielded ceftiofur.
The only known method for the preparation of Furaca is taught by Sacks et al in U.S. Pat. No. 4,937,330. Sacks teaches an aqueous solution of sodium 2-thiofuroate of the formula 
to be reacted with 7-aminocephalosporonic acid at 65xc2x0 C. at pH of 6.4 +/xe2x88x920.2 resulting in a slurry which is adjusted to a pH of 5.0, filtered and washed successively with acetone and heptane to obtain a light colored product. The yield of this reaction is not stated.
The Sacks procedure has certain disadvantages, in that it results in impure Furaca in a low yield. Further, the product obtained is colored and contains unreacted 7-aminocephalosporanic acid. This product is not suited or ill-suited for subsequent 7-acylation to produce ceftiofur. The displacement of the acetoxy group of a cephalosporin by a sulfur nucleophile or its salt in an aqueous medium at elevated temperature (65xc2x0 C.) and near neutral to basic pH is generally destructive to the cephalosporin nucleus and is accompanied by the formation of highly colored impurities. Such a product prepared in this taught manner often requires extensive costly purification.
In addition, the displacement of acetoxy group of a cephalosporanic acid by a sulfur nucleophile in an organic solvent under essentially anhydrous conditions is well documented in literature and in U.S. Pat. No. 4,144,391. Further, it is known from German Offenlegungsschrift 2,804,896 that 7-amino-3-(substituted thiomethyl)-3-cephem-4-carboxylic acids can be prepared by reacting 7-aminocephalosporanic acid with thiol compound in the presence of boron trifluoride. If 2-thiofuroic acid of the formula 
is employed as the thiol compound in the process, with the usual acetonitrile solvent, the reaction is complicated by the formation of desacetyl-7-aminocephalosporanic acid lactone of the formula 
and considerable amount of other unidentified impurities.
Above discussion represents the difficulties with the current art of making Furaca and it is in light of these difficulties that the present invention finds a new route to making Furaca of high purity and high yield.
The present invention provides a novel method of preparation of Furaca of high purity (98-99%) and in good yield (85-88%) by the novel use of boron trifluoride in ethyl acetate. Furaca so obtained can be preferably used for the preparation of antibacterial ceftiofur.
Based on our related art disclosure in the background, the present inventors have conducted extensive experimentation with an intention to overcome the difficulties of producing Furaca in high yields and high purity. We have unexpectedly found that such a novel nucleophilic displacement proceeds well in the presence of boron trifluoride in ethyl acetate solvent giving a ceftiofur intermediate of purity of 98-99% with a color rating of 0.04-0.08 (1% solution, 420 nm). The invention further advantageously uses solution of 2-thiofuric acid in ethyl acetate having water to the extent of 4% w/w. Use of a such a solution avoids the isolation of labile 2-thiofuric acid in an anhydrous form reducing the number of process steps increasing safety and cost-effectiveness.
In accordance with the present invention, there is provided a new process for producing Furaca by reacting 7-aminocephalosporanic acid with 2-thiofuroic acid in presence of boron trifluoride. As a rule, boron trifluoride is used in molar excess, 3 to 7 moles of boron trifluoride per mole of 7-aminocephalosporanic acid. The reaction is effected in ethyl acetate in the temperature range of 10xc2x0 C. to 50xc2x0 C., preferably between 30xc2x0 C. to 35xc2x0 C.
According to the present invention, the boron trifluoride content in ethyl acetate is about 32% w/v. However, varying concentrations can be used depending upon the choice of solvent medium without affecting the final outcome of the process. Typical solvents that can be used are methyl acetate, ethyl acetate, n-butyl acetate and isopropyl acetate. The reaction can be continued until the content of unreacted 7-aminocephalosporanic acid is less than 1% by HPLC analysis. This degree of conversion usually takes about 3 to 5 hours. After the reaction is completed as per HPLC analysis, the reaction mixture is diluted with cold water and subsequently the pH is adjusted with a suitable base such as triethylamine, tributylamine but preferably aqueous ammonia upon which the reaction product precipitates and is obtained in the high purity and yield mentioned before.
The following three examples represent our best mode in our experiments conducted that serves to illustrate our invention without limiting it.